The broad, long-term objective of this research is to find a better therapeutic strategy for preventing neurodegeneration (neuronal damage and cell death) associated with recurring uncontrolled seizures or epilepsy. The immediate goal of this project is to characterize the effects of alpha-1 adrenergic receptor (alpha1AR) activation on interneurons. Many of the currently employed antiepileptic drugs (AEDs) enhance gamma- aminobutyric acid (GABA)-mediated inhibition. The major source of GABA, the predominant inhibitory neurotransmitter in the brain, is a small population of inhibitory cells known as interneurons. Many of the traditional AEDs (e.g., phenobarbital) do not target interneurons, but rather potentiate actions of GABA at the level of the GABAA receptor. Several of the new, more effective second generation AEDs (e.g., gabapentin) appear to act by increasing the amount of GABA available, either by enhancing its synthesis or by inhibiting its catabolism or reuptake. However, none of these AEDs directly activate interneurons. Several lines of evidence indicate that alpha1AR activation is potently antiepileptogenic. The mechanism underlying this effect is unknown. Preliminary studies suggest that alpha1AR activation excites a subpopulation of interneurons leading to enhanced GABA release. This finding may be very important and suggests that selective alpha1AR activation of inhibitory GABAergic interneurons may provide a novel therapeutic strategy for the prophylaxis of seizures and neurodegeneration. This study will test this hypothesis. Using a cross-disciplinary approach combining electrophysiological, molecular biological, and neuroimaging techniques, this project will address these specific aims: 1) characterize the effects of alpha1AR activation on discrete populations of interneurons; 2) identify the particular subtype of alpha1AR mediating these responses; 3) ascertain the connectivity, neurochemistry and synaptological profile of alpha1AR-activated interneurons; and 4) examine the functional consequences of alpha1AR activation on neuronal excitability. The information derived from this research not only will yield important insights into the anatomy, physiology and pharmacology of interneurons, but also may lead to the development of a new class of AEDs with improved neuroprotective actions and enhanced efficacy for treating epilepsy.